Severe early‐onset manifestations of pseudoxanthoma elasticum resulting from the cumulative effects of several deleterious mutations inENPP1,ABCC6andHBB: transient improvement in ectopic calcification with sodium thiosulfate

Abstract

Summary Pseudoxanthoma elasticum (PXE) is a rare disorder characterized by fragmentation and progressive calcification of elastic fibres in connective tissues. Overlap has been reported between the inherited PXE phenotype associated with ENPP1, ABCC6 or NT5E mutations and acquired PXE clinical manifestations associated with haemoglobinopathies induced by HBB mutations. No treatment is currently available for PXE. A young boy presented with severe early‐onset systemic calcifications occurring in the skin as elastosis perforans serpiginosa (EPS) and in the arteries, causing mesenteric and limb ischaemia. Analyses revealed deleterious ABCC6, ENPP1 and HBB mutations. The diagnosis of severe PXE was retained and we have coined the term ‘PXE+ syndrome’ to describe the cumulative effects of the various mutations in this uncommon phenotype. Given the severity, rapid progression and a potentially fatal prognosis, intravenous sodium thiosulfate (STS) was initiated at 25 g three times weekly for 6 months. Numerous side‐effects prompted dosage adjustment to 10 g intravenously daily. Treatment efficacy was evaluated at 6 months. Asthaenia, anorexia and pre‐/postprandial pain had subsided, entailing weight gain. Abdominal EPS had diminished. Calcific stenosis of the coeliac and mesenteric arteries was no longer detectable on arterial ultrasonography. Follow‐up revealed only transient efficacy of STS. Discontinuation of treatment to evaluate the persistence of effects resulted in relapse of the initial symptomatology after 4 months. STS efficacy is conceivably due to strong antioxidant properties and chelation of calcium to form soluble calcium thiosulfate complexes. This case is suggestive of PXE+ syndrome for which STS may represent potential treatment in severe cases. What's already known about this topic? Generalized arterial calcification of infancy may occur in association with ABCC6 mutations and pseudoxanthoma elasticum (PXE) can be linked to ENPP1 mutations. A PXE‐like phenotype has also been reported in a subset of patients with inherited haemoglobinopathies, namely sickle cell disease or β‐thalassaemia, related to HBB mutations. To date, there is still no cure for PXE. What does this study add? We report a severe case of PXE resulting from the cumulative effects of several deleterious mutations in ENPP1, ABCC6 and HBB. We suggest the term ‘PXE+ syndrome’ to describe such patients. Sodium thiosulfate therapy could represent a potential option in severe cases of PXE+ syndrome.

Relationship Between Mitochondrial Structure and Bioenergetics in Pseudoxanthoma elasticum Dermal Fibroblasts

“…Although a number of genes may be involved (Li Q. et al, 2009;Omarjee et al, 2019;Boraldi et al, 2020a), PXE is mostly associated with ATP-binding cassette sub-family C member 6 (ABCC6) mutations (Le Saux et al, 2000), even though ABCC6 is not expressed at the protein level in cells of tissues undergoing calcification (Matsuzaki et al, 2005). It was therefore proposed to consider PXE as a metabolic disease (Jiang et al, 2009), leaving questionable the role of mesenchymal cells within this context.…”

The pathogenic p.R391G ABCC6 displays incomplete penetrance implying the necessity of an interacting partner for the development of pseudoxanthoma elasticum

“…In the cohort we only included patients of known ethnic origin and familial relationship, and with two identified ABCC6 variants considered to be disease-causing at the time of diagnosis. Importantly, patients with only one identified ABCC6 pathogenic variant were not included in the database even though digenic inheritance of PXE was reported earlier (36-38). Altogether 590 probands with European ancestry from three different countries (Belgium, France, and Italy (27, 28)) were included (Supplementary Table 1).…”

“…Only patients of known ethnic origin, familial relationship, and with two identified ABCC6 variants considered to be disease-causing at the time of diagnosis were included in our cohort, which contained 216 different variants including missense, non-sense, frameshift variants and large deletions (Figure 1A and Supplementary Table 1B). (Uitto, Li, and Jiang 2010;Nitschke et al 2012;Omarjee et al 2019).…”

ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions

“…For the most part, PXE is a monogenic disease caused by mutations in ABCC6 . However, other than the cases associated with ENPP1 mutations [ 17 ], PXE manifestations can arise from multifactorial inheritance [ 58 , 59 ], environmental exposure [ 60 , 61 , 62 , 63 ] or secondary to β-thalassemia and sickle cell anemia [ 64 ]. β-thalassemia (MIM 141900) is a monogenic disorder caused by mutations in the β- globin gene that leads to the underproduction of β-globin chains.…”

“…It is now approved for the treatment of certain rare medical conditions notably calciphylaxis [ 214 ]. For this reason, intravenous sodium thiosulfate was recently administered to a single PXE patient with polygenic inheritance and severe early-onset manifestations [ 59 ]. This treatment achieved a remarkable regression of calcific stenosis in the coeliac and mesenteric arteries.…”